Nitroxyl (HNO), a potential heart failure therapeutic (Paolocci N., Saavedra W. F., Miranda K. M., Martignani C., Isoda T., Espey M. G., Hare J. M., Fukuto J. M., Feelisch M., Wink D. A., Kass D. A. Proc. Natl. Acad Sci. U.S.A. 2001, 98, 10463-10468; and Feelisch, M. Proc. Natl. Acad. Sci. U.S.A. 2003, 100, 4978-4980), is known for its high reactivity. It spontaneously dimerizes to yield hyponitrous acid, which subsequently dehydrates to form nitrous oxide (N2O) (Shafirovich, V.; Lymar, S. V. Proc. Natl. Acad Sci. U.S.A. 2002, 99, 7340-7345; Fukuto, J. M.; Bartberger, M. D.; Dutton, A. S.; and Paolocci, N.; Wink, D. A.; Houk, K. N. Chem. Res. Toxicol. 2005, 18, 790-801). Due to HNO's inherent chemical reactivity, it cannot be used directly, and therefore, donors are needed for its in situ generation. Beyond Angeli's salt (AS), Piloty's acid (PA), acyloxy nitroso (AcON) compounds, (hydroxylamino)pyrazolone (HAPY), and (hydroxylamino)barbituric acid (HABA) derivatives, only a limited number of physiologically compatible HNO donors have been reported (Nakagawa, H. J. Inorg. Biochem. 2013·118·187-190; Nakagawa, H. Nitric oxide 2011. 25, 195-200; Guthrie. D. A.; Ho, A.; Takahashi, C. G.; Collins, A.; Morris, M.; Toscano, J. P. J. Org. Chem. 2015, 80, 1338-1348; and Guthrie, D. A.; Nourian, S.; Takahashi, C. G.; Toscano, J. P. J. Org. Chem. 2015, 80, 1349-1356).
One of the primary strategies for HNO generation is based on hydrolysis of nitrosocarbonyl intermediates. In 1992, N,O-bis-acylated derivatives of N-hydroxycyanamide were reported by Nagasawa et al., as HNO donors, but only under enzymatic or basic conditions (Nagasawa, H. T., Lee, M. C.; Kwon, C. H.; Shirota, F. N.; DeMaster. E. G.; Alcohol 1992, 9, 349-353). Along with HNO, toxic cyanide is one of the hydrolysis byproducts. Other non-toxic leaving groups are desired for physiologically compatible HNO applications. O-acylated hydroxamic acids with arenesulfonyl leaving groups as HNO donors also have been reported (Lee, M. J. C.; Nagasawa, H. T.; Elberling, J. A.; DeMaster. E. G. J. Med. Chem. 1992, 35, 3648-3652; and Fukuto, J. M.; Hszieh, R.; Gulati, P.; Chiang, K. T.; Nagasawa, H. T. Biochem. Biophys. Res. Commun. 1992, 187, 1367-1373). These compounds generate HNO upon hydrolysis of the nitrosocarbonyl intermediate under basic conditions. Since these reported donors generated less than 5% HNO at neutral pH, more reactive donors are needed for efficient HNO generation. Recently, modified N,O-bis-acylated hydroxylamine derivatives with arenesulfonyl leaving groups have been reported (Sutton, A. D.; Williamson, M.; Weismiller, H.; Toscano, J. P. Org. Lett. 2012, 14, 472-475). Mechanistic studies revealed that the decomposition chemistry of these donors is more complicated than preliminarily expected. These compounds generate nitrosocarbonyl species under physiological conditions, and upon further hydrolysis release HNO without enzymatic activation; but amide hydrolysis and acyl migration were two other pathways that compete with HNO generation. Therefore, a need remains for compounds that generate HNO in excellent yield, under non-enzymatic, physiologically relevant conditions, without producing toxic byproducts.
Citation of any reference in Section 1 of this application is not to be construed as an admission that such reference is prior art to the present application.